Background & Aims
Oral mucositis (OM) commonly impacts patients treated with radiation therapy (RT) for cancers of the head and neck (HNC). Among patients receiving standard concomitant chemoradiation (CRT), more than two-thirds develop ulcerative OM of such severity as to negatively impact diet and increase the frequency of treatment breaks, need for parenteral nutrition, and use of healthcare resources.[1,2] While the pathobiology underlying OM is complex, evidence suggests that the oral microbiome may contribute to its severity and course.[3,4] In this analysis, which is a part of ARMOR-Trial NCT03843554, we evaluated the effects of targeted dental prophylaxis and oral mucosal deterging intervention (OMDP) during RT on pain, and profiled genetic signatures from peripheral blood before RT (baseline) and changes in cytokine expressions in saliva after RT that were associated with pain in each study arm.
Methods
The ARMOR trial recruited HNC patients who were expected to receive at least 5000 cGy of RT to the oral or oropharyngeal mucosa. Participants were randomized into the test group receiving an enhanced oral care intervention (OMDP arm) or the control (standard arm) receiving regular oral care. Whole blood total RNA at baseline (before RT) was subjected to RNA-seq analysis. Differentially expressed genes (DEGs) were identified between the pain group or no pain group assessed by the EORTC QLQ-C30[5] in each study arm with a p-value < 0.05 and |log2 fold change| > 0.5. Biological processes associated with the identified DEGs were determined by Gene Set Enrichment Analysis (GSEA). Stimulated saliva samples and saline oral rinse (for participants with dry mouth) were also collected at the baseline and within a week of RT completion, which were then subjected to Human Cytokine Array Q1 (RayBiotech, Inc., GA, USA) to assess cytokine profiles.
Results
General pain assessed by EORTC QLQ-C30 in the standard arm was significantly higher than in the OMDP arm after RT (p = .005). The study intervention had a positive effect on general pain. The DEG analysis between the pain and no pain groups in each study arm identified 814 OMPD-specific, 269 standard-specific, and 22 shared DEGs. GSEA identified activated gene sets associated with type I interferon, including the “type I interferon signaling pathway” and suppressed “mucosal immune response” and “innate immune response in mucosa” in the pain group in the OMDP arm. These changes were not found in the standard arm. In the saliva samples, IL6 (p = .051) and CCL3 (p = .055) in stimulated saliva trended towards difference between the pain and no pain groups in the OMDP arm. CCL4 in the pain group of the OMDP arm was significantly higher than that in the no pain group (p = .041). In the standard arm, CCL2 in the pain group was significantly lower than in the no pain group (p = .039).
Conclusions
Enhanced oral care effectively reduced pain scores assessed by EORTC QLQ-C30. As biological determinants in the pain group in the OMDP arm, pre-RT activated type I interferon-associated pathways and post-RT upregulated CCL3, CCL4, and IL6 in saliva suggested pre-existing inflammatory responses in non-responders, intensifying neutrophils, monocyte and macrophage recruitment around mucositis.[6-8] We noted baseline mucosal immune response suppression in the pain group in the OMDP arm, suggesting a novel hypothesis: pre-existing immunosuppression may cause inflammation-inducing conditions, such as infection or changes in the oral microbiome, leading to higher pain scores and cytokine inductions among non-responders to enhanced oral care.
References
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Presenting Author
Taichi Goto
Poster Authors
Taichi Goto
PhD
NIH/NINR
Lead Author
Patricia Corby
University of Pittsburgh, School of Medicine, Department of Radiation Oncology
Lead Author
Alexander Lin
University of Pennsylvania, Perelman School of Medicine, Department of Radiation Oncology
Lead Author
John Lukens
University of Pennsylvania, Perelman School of Medicine, Department of Radiation Oncology
Lead Author
Stephen Sonis
Brigham and Women's Hospital and the Dana-Farber Cancer Institute; Primary Endpoint Solutions, LLC
Lead Author
Leorey Saligan
Symptoms Biology Unit, National Institute of Nursing Research, National Institutes of Health
Lead Author
Topics
- Genetics